Design,synthesis and biological evaluation of novel stilbene-based antitumor agents

A series of novel stilbene derivatives has been synthesized and studied with the main goal to investigate SAR of the amino compound 1a, as well as to improve its water solubility, a potentially negative aspect of the molecule that could be a serious obstacle for a pre-clinical development. We have obtained derivatives with good cytotoxic activity, in particular, the derivatives 5c and 6b could represent two novel leads for further investigation. Compound 8b, a morpholino-carbamate derivative, prodrug of 1a, has a very good solubility in water, and is active in suppressing growth of tumor cells at a concentration of 5000 nM, which is a concentration 100 times higher than the parent stilbene 1a.     

Toward a treatment of diabesity: Rational design,synthesis and biological evaluation of benzene-sulfonamide derivatives as a new class of PTP-1B inhibitors

Targeting of protein tyrosine phosphatase-1B (PTP1B) has emerged as a promising strategy for therapeutic intervention of diabetes and obesity. Investigation of new inhibitors with good bioavailability and high selectivity is the major challenge of drug discovery program targeting PTP1B. Therefore, herein, new neutral benzene-sulfonamide containing compounds were designed, synthesized and biologically evaluated as potent PTP1B inhibitors. New series of thiazolidine, oxazolidine, thiazinan, oxazinan, oxazole, thiazole, tetrazole, cyanopyridine, chromenone, and iminochromene of benzene-sulfonamide derivatives (MSE-1 to MSE-15) were synthesized in a good yield under mild condition using sulfadiazine as a starting material. Among the synthesized compounds, MSE-13 and MSE-14 showed the most in vitro potent PTP-1B inhibitory activity (IC₅₀ of 0.88 µM and 3.33 µM, respectively). Animal treatment by the target compounds significantly improved the insulin resistance, diminished plasma glucose level, decreased initial body weight, and normalized the serum lipid profile compared to pioglitazone, a standard PTP1B inhibitor. The molecular modeling study showed a high affinity and selectivity of our synthesized compounds to the active site and B-site of PTP1B holding hydrogen bonding, hydrophobic, and electrostatic interactions. Furthermore, Electrostatic Surface Potential (ESP) and HOMO/LUMO analysis indicated the importance of sulfamoyl moiety for PTP1B binding. In silico ADME predictions of such compounds also showed the promising pharmacokinetic and physicochemical properties. The proposed compounds could be considered a lead inhibitory scaffold to PTP1B.     

Design,synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents

In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2′,5′-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC₅₀ = 17–130 nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway.     

Design,synthesis, and biological evaluation of biotinylated colchicine derivatives as potential antitumor agents

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.     

Antitumor agents 251: synthesis, cytotoxic evaluation, and structure-activity relationship studies of phenanthrene-based tylophorine derivatives (PBTs) as a new class of antitumor agents

Polar phenanthrene-based tylophorine derivatives (PBTs) were designed, synthesized and evaluated as potential antitumor agents. These compounds contain a core phenanthrene structure and can be synthesized efficiently in excellent yield. The newly synthesized PBTs were evaluated for cytotoxic activity against the A549 human cancer cell line. Among them, N-(2,3-methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-L-2-piperidinemethanol (34) and N-(2,3-methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-5-aminopentanol (28) showed the highest potency with IC50 values of 0.16 and 0.27 microM, respectively, which are comparable to those of currently used antitumor drugs. A structure-activity relationship (SAR) study was also explored to facilitate the further development of this new compound class.     

Design,synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22–33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb’s amide formation technique, using SmCl₃ as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute’s (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.     

Rational design,synthesis and biological profiling of new KDM4C inhibitors

The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.     

alpha(1)-Adrenoceptor antagonists. Rational design, synthesis and biological evaluation of new trazodone-like compounds

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.     

Rational design,synthesis and biological evaluation of ubiquinone derivatives as IDO1 inhibitors

Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive therapeutic target for the treatment of cancer, chronic viral infections and neurological disorders characterized by pathological immune stimulation. Herein, a series of known metal-chelating ubiquinone derivatives were designed, synthesized and evaluated for the IDO1 inhibiting activities. The docking studies showed that the compounds 11, 16, 18 and coenzyme-Q1 exhibited different binding modes to IDO1 protein. Among these compounds, the most active compound is 16d with an IC₅₀ of 0.13 μM in enzymatic assay. The results reveal that a possible halogen bonding interaction between the bromine atom (3-Br) and Cys129 significantly enhances the inhibition activity against IDO1. This study provides structural insights of the interactions between ubiquinone analogues and IDO1 protein for the further modification and optimization.     

Rational design,synthesis, and biological evaluation of novel growth hormone releasing factor analogues

Since its initial discovery in 1982, growth hormone-releasing factor (GRF) has been the subject of intense investigation. This interest was prompted by the potential application of GRF for Stimulating growth in dwarf humans and for performance enhancement in livestock. Substantial research has been focused upon the development of potent, long-acting analogs as therapeutics. Herein is described a summary of the cumulative efforts of various laboratories endeavoring in this quest. The rationale utilized in GRF analog development is discussed: (1) determination of bioactive core. (2) evaluation of secondary structure, and (3) elucidation of degradation pathways (chemical and enzymatic). Using this information, several series of linear (unnatural and natural sequence) and cyclic GRF analogs were designed, synthesized, and evaluated. Stimulated by the constraints of commercial production, innovative, alternative methods of synthesis were explored: solid-phase, solution-phase, enzymatic, and recombinant. To date, the most promising candidate for drug development is [His¹, Val², Gln⁸, Ala¹⁵, Leu²⁷]-hGRF(1-32)-OH. This natural sequence analog, consisting of rodent and human sequences, incorporates the bioactive core, preferred secondary structure, resistance to chemical and enzymatic degradation: with the added benefit of amenability to large-scale recombinant synthesis. © 1994 John Wiley & Sons, Inc.     

Design,synthesis, and biological activity of Plastoquinone analogs as a new class of anticancer agents

In this paper, based on Plastoquinone (PQ) analogs possessing substituted aniline containing alkoxy group(s), new 2,3-dimethyl-5-amino-1,4-benzoquinones (PQ1-15) were designed and synthesized in either two steps or one-pot reaction. Specifically, the substituted amino moiety containing mono or poly alkoxy group(s) with various positions and groups were mainly explored to understand the structure-activity relationships for the cytotoxic activity against three human cancer cell lines (K562, Jurkat, and MT-2) and human peripheral blood mononuclear cells (PBMC). PQ2 was found to be most effective anticancer compound on K562 and Jurkat cell lines with IC₅₀ values of 6.40 ± 1.73 μM and 7.72 ± 1.49 μM, respectively. Interestingly, the compound was non-cytotoxic to normal PBMC and also MT-2 cancer cells. PQ2 which showed significant selectivity in MTT assay was chosen for apoptotic/necrotic evaluation and results exhibited that it induced apoptosis in K562 cell line after 6 h of treatment. PQ2 showed anti-Abelson kinase 1 (Abl1) activity with different inhibitory profile than Imatinib in the panel of eight kinases. The binding mode of PQ2 into Abl ATP binding pocket was predicted in silico showing the formation of some key interactions. In addition, PQ2 induced Bcr-Abl1 mediated ERK pathway in human chronic myelogenous leukemia (CML) cells. Furthermore, DNA-cleaving capability of PQ2 was clearly enhanced by iron (II) complex system. Afterward, a further in silico ADMET prediction revealed that PQ2 possesses desirable drug-like properties and favorable safety profile. These results indicated that PQ2 has multiple mechanism of action and two of them are anti-Bcr-Abl1 and DNA-cleaving activity. This study suggests that Plastoquinone analogs could be potential candidates for multi-target anticancer therapy.     

Design,synthesis, and biological evaluation of 1,9-diheteroarylnona-1,3,6,8-tetraen-5-ones as a new class of anti-prostate cancer agents

In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner–Wadsworth–Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G₀/G₁ phase.     

Quinazoline-sulfonamides as potential antitumor agents: synthesis and biological testing

Abstract

New series of quinazoline containing sulfonamide derivatives were prepared and screened for their antitumor activity. Four human cancer cell lines, namely, hepatoma cancer cell line (HepG2), breast cancer cell line (MCF-7), cervix cancer cell line (HeLa) and colon cancer cell line (HCT-8), were used to measure the cytotoxic activity. Compounds 8 and 21 exhibited remarkable antitumor activity almost similar to that of the standard drug (doxorubicin). Six compounds 16, 22, 23, 29, 30 and 33, showed considerable activity and few compounds were totally inactive.     

Design, synthesis, and biological evaluation of new mitonafide derivatives as potential antitumor drugs

A series of potential DNA-binding antitumor agents, 2-[omega-(alkylamino)alkyl]-6-{[omega-(alkylamino)alkyl]amino}-1H-benzo[de]isoquinolin-1,3(2H)-diones and 1,7-bis{6-[(omega-(dimethylamino)alkyl)amino]-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl}-4-methyl-4-azaheptanes, have been prepared as mitonafide derivatives. Their DNA-binding ability and cytotoxic activity have been evaluated. Some of the target compounds have shown high DNA affinity as well as relevant cytotoxic properties.     

Design,synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents

Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MTT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC₅₀ = 16.57, 5.45, 4.42 and 5.16 μM) and 33e (IC₅₀ = 20.14, 6.71, 4.62 and 5.62 μM) showed excellent anti-proliferative activities on MCF-7, HepG2, HCT116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties.     

Isoindolone derivatives, a new class of 5-HT2C antagonists: synthesis and biological evaluation

Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon-carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.     

Reverse-benzamidine antimalarial agents: Design,synthesis, and biological evaluation

In the frame of the development of bis-cationic choline analogs, the RSA of bis-N-alkylamidines were studied and a new series of reverse-benzamidine derivatives was designed. Contrary to the lipophilicity, the basicity of alkylamidine compounds directly influences their antimalarial potencies.     

Synthesis and biological evaluation of indolyl glyoxylamides as a new class of antileishmanial agents

A series of indolylglyoxylamide derivatives have been synthesized and evaluated in vitro against amastigote form of Leishmania donovani. Compound 8c has been identified as the most active analog of the series with IC₅₀ value of 5.17 μM and SI value of 31.48, and is several folds more potent than the standard drugs sodium stilbogluconate and pentamidine.     

Naphthyl phosphoramidate derivatives of BVdU as potential anticancer agents: design, synthesis and biological evaluation

The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in this work a new series of derivatives containing naphthol as aryl masking group on the phosphate moiety, which has shown a significant increase in anticancer activity in preliminary biological evaluations.     

Triazole incorporated pyridazinones as a new class of antihypertensive agents: design, synthesis and in vivo screening

A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-4u) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k showed appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol.